The disclosures of all patents mentioned are incorporated by reference.
With respect to intraoral administration, the most pertinent prior art reference known to applicants is U.S. Pat. No. 4,229,447 to Porter which discloses a method of administering certain benzodiazepines sublingually and buccally. Porter specifically mentions the sublingual or buccal administration of diazepam, lorazepam, oxazepam, temazepam and chlorodiazepoxide and describes two generic structures of benzodiazepines that may be administered sublingually or buccally.
The compound shown below is contemplated by the generic structures in Porter. All of the benzodiazepines disclosed and the generic structure described in Porter are BZ.sub.1 -BZ.sub.2 receptor non-specific since they lack the trifluoro ethyl group pendant at the N position of the "B" ring which confers BZ.sub.1 specificity. ##STR1##
Porter's method is based on the rapid buccal or sublingual absorption of selected benzodiazepines to attain effective plasma concentration more rapidly than oral administration. In contrast, while parenteral administration provides a rapid rise of blood levels of the benzodiazepines, parenteral administration is frequently accompanied by pain and irritation at the injection site and may require sterilization of the preparatives and the hypodermic syringes.
Porter points out that the intraoral, i.e., buccal or sublingual administration, of lipid soluble benzodiazepines results in therapeutic levels resembling parenteral administration without some of the problems associated with parenteral administration. Porter's administration technique for benzodiazepines in general builds on a long established knowledge in pharmacology that a drug absorbed in the intraoral route gives rise to more rapid absorption than the same drug swallowed into the stomach. What is not recognized by Porter, however, are concerns with first-pass metabolism which can be avoided either with the sublingual or parenteral route of drug administration of certain benzodiazepines.
Porter does not recognize that first-pass metabolism designates the drug intestinal absorption with subsequent entry directly into the portal blood supply leading to the liver and that the liver in turn rapidly absorbs and metabolizes the drug with its first-pass high concentration through the liver. In addition, some first pass metabolism may occur during the absorption process into the intestine. Thus, large amounts of the drug may never be seen by the systemic circulation or drug effect site. Porter further does not recognize that the more rapid metabolism via the first-pass metabolism route can lead to accelerated desalkylation with formation of high plasma concentrations of an unwanted metabolite.
Thus, applicants' concern with avoiding the degradation of the parent compound and its desired positive effect and avoiding the metabolism of the parent compound to an undesired metabolite is neither recognized nor addressed by Porter, who only addresses the ability of the oral mucous membranes to absorb certain benzodiazepines fast and achieve high plasma levels of these benzodiazepines quickly.
The specific drug for which this phenomenon was demonstrated by Porter was lorazepam which has a simple metabolism that results in it not being metabolized to active compounds. Also, and very significantly, the issue of human nervous system receptor specificity and activation for BZ.sub.1 and BZ.sub.2 type receptors is not recognized by Porter either generally or with reference specifically to trifluorobenzodiazepines.
U.S. Pat. No. 3,694,552 to Hester discloses that 3-(5-phenyl-3H-1,4-benzodiazepine-2-yl)carbazic acid alkyl esters, which are useful as sedatives, hypnotics, tranquilizers, muscle relaxants, and anticonvulsants, can be administered sublingually. Subsequently issued U.S. Pat. No. 4,444,781 to Hester specifically teaches that 8-chloro-1-methanol-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiaz epine therapeutic compounds, which are useful as soporifics, can be suitably prepared for sublingual use.
Also, U.S. Pat. No. 4,009,271 to vonBebenburg et al. discloses that 6-aza-3H-1,4-benzodiazepines and 6-aza-1,2-dihydro-3H-1,4-benzodiazepines (which have pharmacodynamic properties including psychosedative and anxiolytic properties as well as antiphlogistic properties) can be administered enterally, parenterally, orally or perlingually.
The chemical formula of nefazodone is 2-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl-5-ethyl-2,4-dihydro-4-(2-phe noxyethyl)-3H-1,2,4-triazol-3-one hydrochloride and it is abbreviated as NEF.
Patients with obsessive compulsive disorder respond to meta-chlorophenylpiperazine (abbreviated as mCPP), an undesirable metabolite of NEF, by becoming much more anxious and obsessional, as reported by Zohar et al. in "Serotonergic Responsivity in Obsessive Compulsive Disorder: Comparison of Patients and Healthy Controls", Arch. Gen. Psychiatry, Vol. 44, pp. 946-951 (1987). The peak in the anxiousness and obsessional behaviors is observed within 3 hours of mCPP administration and the duration of the worsening ranges from several hours to as much as 48 hours. Much more significantly, mCPP induced a high rate of emergence of entirely new obsessions or the reoccurrence of obsessions that had not been present in the patients for several months. Patients also reported being more depressed and dysphoric.
More specifically, Zohar et al. administered 0.5 mg/kg of mCPP orally to subjects in eliciting their obsessional symptoms. The peak plasma concentration in the control patients was 33.4.+-.17.34 ng/ml, whereas, in the obsessional patients, the peak plasma concentration inducing the obsessional behavior was 26.9 ng/ml.+-.12.33.
Furthermore, Hollander et al., in "Serotonergic Noradrenergic Sensitivity in Obsessive Compulsive Disorder: Behavioral Findings", Am. J. Psychiatry, Vol. 1945, pp. 1015-1017, (1988), have reported many of these obsessional worsening effects in obsessive compulsive patients.
Additionally, Kahn et al., in "Behavioral Indications for Serotonin Receptor Hypersensitivity in Panic Disorder", Psychiatry Res., Vol. 25, pp. 101-104 (1988), have reported mCPP induces anxiety in a group of panic disorder patients.
Moreover, Walsh et al., as reported in "Neuroendocrine and Temperature Effects of Nefazodone in Healthy Volunteers", Biol. Psychiatry, Vol. 33, pp. 115-119 (1933), administered oral doses of 50 mg and 100 mg of NEF to normal subjects and measured NEF and its metabolite mCPP. For the 50 mg dose, the NEF/mCPP area under the curve (abbreviated as AUC) ratio was 1.58. For the 100 mg dose, the AUC ratio was 1.63, indicating that within the first 3 hours, NEF is substantially metabolized to MCPP at levels considerably above the mCPP levels that Zohar et al., supra, found to induce anxiety and obsessional states in susceptible individuals.
In studies in dogs, intravenous dosing of NEF reduced plasma mCPP Cmax by 50% from that found with oral dosing, as reported by Shukla et al., in "Pharmacokinetics, Absolute Bioavailability, and Disposition of [.sup.14 C] Nefazodone in the Dog", Drug Metab. Disposition, Vol. 21, No. 3, pp. 502-507 (1993).
Also, a discussion of bupropion and its three major metabolites, erythrohydrobupropion, hydroxybupropion, and threohydrobupropion, as well as the strong relationship of higher hydroxybupropion metabolite concentrations in therapeutically non-responding patients in contrast to responders, can be seen in Posner et al., "The Disposition of Bupropion and Its Metabolites in Healthy Male Volunteers after Single and Multiple Doses", Vol. 29, Eur. J. Clin. Pharmacol., pp. 97-103 (1985) and Bolden et al., "Bupropion in Depression", Vol. 45, Arch. Gen. Psychiatry, pp. 145-149 (Feburary 1988). Hydroxybupropion, therefore, represents an unwanted metabolite.
Background information with respect to skin administration of drugs is as follows.
Highly lipid soluble substances are absorbed through the skin and even are the basis for the toxicity for such lipid soluble drugs, for instance, insecticides and organic solvents. Absorption through the skin can be enhanced by suspending the drug in an oily vehicle and rubbing it onto the skin, a method known as inunction.
A variety of improvements in transdermal administration of drugs has transpired over the last few years.
For example, ultrasound mediated transdermal delivery, in which low frequency ultrasound application increases the permeability of the skin to many drugs including higher molecular weight drugs, was recently described by Mitragotri, Blankschtein, and Langer in "Ultrasound-Mediated Transdermal Protein Delivery", Science, 269:850-853 (1995).
In addition, when ionizable drugs such as dexamethasone sodium phosphate or lidocane hydrochloride are used, the electro-transport system of iontophoresis can be used to drive the drugs through the skin such as in the use of the PHORESOR.RTM. made by IOMED. Also, Alza Corporation has also been active in developing electro-transport systems for drug delivery. (See, Alza U.S. Pat. Nos. D384,745 issued Oct. 7, 1997; D372,098 issued Jul. 23, 1996; U.S. Pat. Nos. 5,629,019 issued May 13, 1997; and 566,817 issued Sep. 16, 1997.
The advantages of skin administration to the systemic circulation include:
1) bypassing the gastrointestinal portal vein entry into the liver and its first-pass metabolism, PA1 2) sustained blood levels without multiday dosing, and PA1 3) blood concentrations of drug controllable within and between patients in a narrow range.
See, Shaw, J. E. and Chandrasekaran, S. K., "Skin as a Mode for Systemic Drug Administration", Greaves, M. W. and Shuster, S. (eds.), Pharmacology of the Skin II, Springer-Verlag:New York, pp. 115-122 (1989).
Background information with respect to skin patches is described in U.S. Pat. No. 4,920,989 to Rose, Jarvik, and Rose, and in U.S. Pat. No. 5,016,652 to Rose and Jarvik, both of which involve administration of nicotine by way of a skin patch. See also, Southam, M. A., "Transdermal Fentanyl Therapy: System Design, Pharmacokinetics and Efficacy", Anti-Cancer Drugs, 6 Suppl. 3:29-34, (1995) as another example of skin patches.
Of the rapid development of techniques for administering drugs by skin patches, one improvement is the development by Fuisz Technology LTD of a melt spinable carrier agent such as sugar which is combined with a medicament and then converted to a fiber for by melt-spinning. (See, U.S. Pat. No. 4,855,362, entitled "Rapidly Dissolvable Medicinal Dosage Unit and Method of Manufacture".) This facilitates dissolving the medication onto any surface area when wetted such as with skin moisture. It is also readily applicable to sublingual or buccal administration.
These skin delivery systems are well known to those practiced in the art of clinical pharmacology.
More specifically in connection with the additional information in the instant continuation-in-part patent application vis-a-vis deprenyl are U.S. Pat. Nos. 4,868,218 and 4,861,800, both issued in 1989 to Buyske. The former discloses the MAO inhibitor type B drug levo-deprenyl being used in the treatment of mental depression in a formulation applied to the skin of a human patient. The latter discloses the MAO inhibitor type B drug levo-deprenyl being used for the treatment of Parkinson's disease or Alzheimer's disease in a formulation applied to the skin of a human patient.
Background information with respect to inhalation of drugs is as follows.
Inhalation techniques for administering drugs have been known for centuries. Witness the use of smoking to administer opiates and nicotine.
Also, inhalation of gases is a classical means of inducing surgical anesthesia and as well volatile drugs may be inhaled in this manner.
In another embodiment of the present invention, the focus is on inhalation administration of medicaments, particularly via inhalators, such as for dry powders or aerosols. Inhalation drug administration provides a means of bypassing the gastrointestinal portal vein entry first-pass metabolism and as well provides a means of rapid access to the general circulation. See, Benet, L. Z., Kroetz, D. L. and Sheiner, L. B., "Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination", Hardman, L. G. et al. (eds), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9.sup.th Ed, McGraw-Hill:New York, pp. 3-27, (1996).
Drugs delivered from inhalators are airborne fine particles. The particles may be aerosolized suspensions (admixed with a propellant gas, i.e., a chlorofluorocarbon) or may be dispersed powders (generally admixed with an excipient). These particles may be either liquids or solids and are defined by the mass median aerodynamic diameter (MMAD). Thus, solid particulate(s) and liquid droplet(s) with the same unit density have the same average rate of settling (e.g., in the lungs).
The size of the airborne particles is important. If they are larger than 10 micrometers diameter, they are unlikely to reach the lungs for deposit. If they are smaller than 0.5 micrometers diameter, they may be exhaled again.
One of the problems with inhalation delivery is that only approximately 10-20% of the drug is delivered to the lung alveoli. The rest is deposited into the oro-pharynx. If this were swallowed, it would go into a gastrointestinal absorption portal vein liver entry and metabolism pathway. Thus, mouth rinsing is frequently recommended.
In the present invention, this deposition into the oropharynx does not present the same type of problem. Since the airborne drug being inhaled is in a fine particle form with the appropriate formulation, it will be rapidly absorbed in the oral cavity if swallowing is delayed as it will with sublingual administration. Thus, inhalation administration presents a combined buccalingual pathway (as well as an oropharyngeal pathway) plus the lung absorption means of bypassing the gastrointestinal liver first-pass metabolism.
There are several inhalator delivery systems contemplated as useful in the present invention.
One is a traditional nebulizer which works via a mechanism similar to the familiar perfume atomizer. The airborne particles are generated by a jet of air from either a compressor or compressed gas cylinder passing through the device. In addition, newer forms utilize an ultrasonic nebulizer by vibrating the liquid at speeds of up to about 1 MHZ.
Another type of inhalator delivery system is the metered dose inhaler (MDI). This has been widely used because of its convenience and usually contains a suspension of the drug in a aerosol propellant. However, the MDI has fallen into disfavor recently due to problems with chlorofluorocarbon propellants causing depletion of the earth's ozone layer, which has led to increased use of still another type of inhalator delivery system, namely the dry powder inhaler.
The typical dry powder inhaler has the appropriate dose often placed in a capsule along with a flow aid or filler excipient, such as large lactose or glucose particles. Inside the device, the capsule is initially either pierced by needles (SPINHALER.RTM.) or sheered in half (ROTOHALER.RTM.). Propellers turning cause the capsule contents to enter the air stream and to be broken up into small particles. (See also, DISKHALER.RTM., TURBUHALER.RTM., plus numerous other dry powder inhalation delivery devices.) For a review, see Taburet, A. M. and Schmit, B., "Pharmacokinetic Optimisation of Asthma Treatment", Clin. Pharmacokinet., 26(5):396-418 (1994).
More recently, Inhale Therapeutic Systems has created an inhalator delivery system that integrates customized formulation and proprietary fine powder processing and packaging technologies with their proprietary inhalation device for efficient reproducible deep-lung delivery. Their process of providing agglomerate composition compounds of units of aggregated fine particles and methods for manufacture and use of the units has recently been covered by a series of patents. The particle size containing the drug is in the optimum range for deep-lung delivery and has a suitable friability range. The U.S. Patents covering these methods include U.S. Pat. Nos. 5,458,135 issued Oct. 17, 1995, 5,607,915 issued Mar. 4, 1997 and 5,654,007 issued Aug. 5, 1997. (See also, U.S. Pat. No. 5,655,516 issued Aug. 12, 1997.)
Other potential improvements of pulmonary inhalation of drugs via an inhalator delivery system include the use of liposomes (microscopic phospholipid vesicles). The liposomal delivery of drugs slows the uptake of drug absorption from the lungs thus, providing a sustained drug release. (See, Hung, O. R., Whynot, S. C., Varvel, J. R., Shafer, S. L. and Mezel, M., "Pharmacokinetics of Inhaled Liposome-Encapsulated Fentanyl", Anesthesiol., 82:277-284 (1995).
The key factor to be considered here is that most inhalation delivery devices are currently used for treatment of lung conditions in which it is important to supply the active drug to a site in the lungs where the drug acts for a period of time before being absorbed into the general circulation. Since the lungs have a surface area of at least the size of a tennis court and a series of thin cell sacks (alveoli) that are highly vascularized, the lungs provide a large surface area for absorption of drugs. However, in the present invention, the inhalation technique provides a means of not only administering drugs to the lungs, but also, because of the small particle size, a means of delivering highly absorbable small particles to multiple sites in the oropharyngeal pathway. Thus, the drug is dispersed to a topographically much larger mucosal absorption area than would occur from sublingual and/or buccal administration, and additionally, provided is the 10-20% absorption by lung administration.
Moreover, general background information with respect to dry powder inhalers can be seen in U. S. Pat. Nos. 2,642,063 to Brown; 3,807,400 to Cocozza; 3,906,950 to Cocozza; 3,991,761 to Cocozza; 3,992,144 to Jackson; 4,013,075 to Cocozza; 4,371,101 to Cane and Farneti; 4,601,897 to Saxton; 4,841,964 to Hurka and Hatschek; 4,955,945 to Weick; 5,173,298 to Meadows; 5,369,117 to Sallmann, Gschwind, and Francotte; 5,388,572 to Mulhauser, Karg, Foxen, and Brooks; 5,388,573 to Mulhauser and Karg; 5,394,869 to Covarrubias; 5,415,162 to Casper, Taylor, Leith, Leith, and Boundy; 5,503,869 to Van Oort; International Publication No. WO 92/00115 to Gupte, Hochrainer, Wittekind, Zierenberg, and Knecht; International Publication No. WO 94/20164 to Mulhauser and Karg; and International Publication No. WO 93/24166 to Wright, Seeney, Hughes, Revell, Paton, Cox, Rand, and Pritchard.
Background information specifically with respect to levo-deprenyl and levo-desmethyl deprenyl, the subject of the additional information in the instant continuation-in-part patent application is as follows.
U.S. Pat. No. 5,792,799 issued in 1998 to ShermanGold discloses the treatment of Parkinson's disease in a human patient by nasal administration, intrapulmonary administration, or parenteral administration of a MAO type A inhibitor, and optionally, the MAO type A inhibitor can be administered in conjunction with a MAO type B inhibitor, such as selegiline, i.e., deprenyl. See, for instance, the paragraph at lines 28-39 of column 4 of '799, especially, line 34 of this paragraph.
Additionally, U.S. Pat. No. 5,380,761 issued in 1995 to Szabo et al. discloses an anhydrous transdermal composition containing racemic N-methyl-N-(1-phenyl-2-propyl)-2-propynyl amine, another chemical name for racemic deprenyl, for treatment of a human patient.
As noted above, U.S. Pat. Nos. 4,868,218 and 4,861,800, both to Buyske, disclose levo-deprenyl in a formulation applied to the skin of a human patient.
Each of U.S. Pat. Nos. 5,792,799, 4,861,800, and 4,868,218 contains a discussion of the "cheese effect" of MAO type A inhibitors. More specifically, MAO type A inhibitors, when given orally to a human patient such as by swallowing, reduce the gut and liver MAO type A enzyme, resulting in a human patient hypertensive crisis following ingestion by the human patient of foods containing high levels of tyramine, such as cheese and red wine; that is, tyramine is not sufficiently metabolized by MAO type A enzyme, resulting in high hypertensive levels of tyramine. Moreover, these patents also recognize that MAO type B inhibitors, such as deprenyl, have only modest effects on tyramine metabolism in the gut and the liver as compared to MAO type A inhibitors.
Similarly, the researchers Lajtha et al. in "Metabolism of (-)-Deprenyl and pF-(-)-Deprenyl in Brain after Central and Peripheral Administration", Vol. 21, No. 10, Neurochemical Research, pp. 1155-1160 (1996) demonstrated in a study that when deprenyl was administered to rats by subcutaneous injection, then the unwanted metabolites of levo-amphetamine and levo-methamphetamine were significantly reduced, especially in comparison to the deprenyl level.
In other words, as reported by Oh et al. in "(-)-Deprenyl Alters the Survival of Adult Murine Facial Motoneurons After Axotomy: Increases in Vulnerable C57BL Strain but Decreases in Motor Neuron Degeneration Mutants", Vol. 38, Journal of Neuroscience Research, pp. 64-74 (1994), oral dosing of mice with deprenyl, because of the nonspecific high first pass metabolism in the liver and the gut results in extremely high levels of the unwanted metabolites, levo-amphetamine and levo-methamphetamine, which themselves can result in neurotoxicity and can reduce the effectiveness of the neuronal protection by deprenyl.
A good discussion of the rapid rise of the unwanted metabolite, levo-methamphetamine, after first pass metabolism, can be seen in Rohatagi et al., "Pharmacokinetic Evaluation of a Pulsatile Oral Delivery System", Vol. 18, No. 8, Biopharmaceutics & Drug Disposition, pp. 665-680 (1997).
Nevertheless, a problem with skin patch administration of deprenyl to a patient is that skin patch administration induces a sustained low level of deprenyl since deprenyl is slowly absorbed from the skin patch. Because deprenyl is an irreversible inhibitor substrate for MAO type B, a high short period of brain levels of deprenyl is the most efficient and most effective means of administration as once deprenyl binds to the enzyme, MAO, deprenyl is irreversibly bound (i.e., inhibits the enzyme) and is not available for egress from the brain to the blood stream with subsequent availability for metabolism.
More specifically, Tarjanyi et al. in "Gas-Chromatographic Study on the Stereoselectivity of Deprenyl Metabolism", Vol. 17, Journal of Pharmaceutical and Biomedical Analysis, pp. 725-731 (1998) demonstrated with PET scanning in human subjects that .sup.11 C-labeled deprenyl had a very fast penetration of levo-deprenyl into the brain, namely that deprenyl entered the brain within seconds and the radioactivity was found to be constant during a 90 minute PET examination. At the same time, the inactive stereoisomer, dextro-deprenyl, which does not have a comparable binding to the enzyme, MAO, was rapidly washed out of the brain. Thus, this irreversible inhibition of MAO type B is induced by the formation of a covalent bond between the flavine group of the enzyme and levo-deprenyl, which prevents levo-deprenyl from brain egress into the peripheral circulation and liver metabolism.
This rapid entry of levo-deprenyl into the brain, as noted by Heinonen et al. in "Pharmacokinetics and Clinical Pharmacology of Selegiline", Chapter 10, Inhibitors of Monoamine Oxidase B, Pharmacology and Clinical Use in Neurodegenerative Disorders, pp. 201-213, Edited by Szelenyi (1993), is due to the high lipophilicity of deprenyl. Heinonen et al. conclude that the bioavailability of levo-deprenyl after oral administration is only about 8%. Therefore, a significant percentage of levo-deprenyl, after oral administration, is rapidly metabolized into unwanted metabolites.
In such degenerative diseases as Parkinson's disease, dopamine neurons degenerate and they are replaced by glial cells possessing MAO type B activity, as reported by Tatton and Chalmers-Redman in "Modulation of Gene Expression Rather than Monoamine Oxidase Inhibition: (-)-Deprenyl Related Compounds in Controlling Neurodegeneration", Vol. 47, No. 6, Supplement 3, Neurology, pp. 171S-183S (December, 1996). Consequently, dopamine modulation in the brain declines in Parkinson's disease and in senescence, and concurrently, an increase in MAO activity develops. The increase in MAO type B activity is thought to be responsible for the oxidative dopamine metabolites that injure neurons. As reported by Strolin-Bendetti and Dostert in "Monoamine Oxidase, Brain Aging and Degenerative Diseases", Vol. 38, No. 4, Biochemical Pharmacology, pp. 555-561 (1989), MAO type B increases with the age of a person, which leads to a rise in hydrogen peroxide that may well contribute to the neuronal damage.
Tatton and Chalmers-Redman, supra, also discuss that levo-deprenyl has been used in combination with levo-dopa therapy, in part to reduce the needed levo-dopa dosage (by reducing dopamine metabolism) and in part to decrease the response fluctuation. As also noted by Tatton and Chalmers-Redman, supra, another action of levo-deprenyl at low levels is that super oxide dismutase, a scavenger of neuronal oxygen radicals, is increased in the striata of rats treated with levo-deprenyl.
Use of levo-deprenyl in combination with levo-dopa therapy is also discussed in U.S. Pat. No. 5,844,003 to Tatton and Greenwood. In addition, this patent mentions several deprenyl analogues, i.e., desmethyl deprenyl, that may also be irreversible inhibitors of MAO type B, accompanied by formation, during metabolism, of unwanted metabolites.
Moreover, as reported by the Parkinson Study Group in "Effects of Tocopherol and Deprenyl on the Progression of Disability in Early Parkinson's Disease", Vol. 328, No. 3, The New England Journal of Medicine, pp. 176-183 (Jan. 21, 1993), levo-deprenyl, when used alone, can slow the time course of Parkinson's disease as judged by the time required for the disease to progress to the point where levo-dopa is required.
The capacity of levo-deprenyl to increase the time to the requirement for levo-dopa therapy in Parkinson's disease is highly statistically significant but appears to wane after a year of treatment. The waning may be due to the actual impairment effects of levo-amphetamine and levo-methamphetamine (or dextro-amphetamine and dextro-methamphetamine, if dextro-deprenyl or a racemic mixture is used), which as noted above can be neurotoxic, but in the case of Parkinson's disease, levo-amphetamine and levo-methamphetamine may actually exhaust the dopamine cells by driving dopamine metabolism to high levels.
Lastly, it is noted that unlike levo-amphetamine and levo-methamphetamine (which are unwanted metabolites of levo-deprenyl) , levo-desmethyl deprenyl is not an unwanted metabolite of levo-deprenyl. Rather, levo-desmethyl deprenyl protects dopamine neurons from N-methyl-D-aspartate receptor-mediated excitotoxic damage. See, Mytilineou et al., "L-(-)-Desmethylselegiline, a Metabolite of Selegeline [L-(-)-Deprenyl], Protects Mesencephalic Dopamine Neurons from Excitotoxicity in Vitro", Vol. 68, No. 1, Journal of Neurochemistry, pp. 434-436 (1997).
The disclosures of all of the cited patents are incorporated herein by reference.